Vitiligo affects 1 percent of the population worldwide. This very common skin affliction is of great significance among dark skinned people in the United States and worldwide. In many countries and societies people with vitiligo are treated as outcasts. We propose that the defenses of melanocytes against cell death are overcome in vitiligo, and must be restored during vitiligo repigmentation. We hypothesize that Insulin-like Growth Factor 1 (IGF-1) is a critical mediator of melanocyte function, stimulating melanocyte movement and proliferation and promoting melanocyte survival by maintaining anti-apoptotic defenses. This proposal will define the IGF-1 anti-apoptotic defenses of melanocytes. Specific Aim 1 will demonstrate that IGF-1 maintains the resistance of human melanocytes to apoptosis and will determine which anti-apoptotic proteins are controlled by IGF-1. Specific Aim 2 will determine which of these IFG-1 effects are mediated through the Ras signaling pathway. Specific Aim 3 will determine whether IGF-1 dependent anti-apoptotic defenses are mediated through PI3K or AKT/PBK. Specific Aim 4 will determine whether intergrin receptors and the IGF-1 receptor act synergistically to control anti-apoptotic defenses in melanocytes. These project is innovative because it: i). Applies modern knowledge of the molecular control of apoptosis and cell death to the study of melanocyte survival, a fundamental biologic feature relevant to human vitiligo, and ii) focuses attention on the role of IGF-1 in melanocyte biology. IGF-1 is a powerful mediator of melanocyte function and mediates crucial survival mechanism in other types of cells. The experiments proposed in this RO3 grant will provide the preliminary data for a future RO1 on IGF-1 as a survival factor in vitiligo. The detailed mechanistic studies of IGF-1 control of melanocyte survival will provide a proper basis for questions concerning the relative role of IGF-1 in melanocyte destruction in vitiligo, and of melanocyte survival during repigmentation of vitiligo.